TMEM16A Ca(2+)-activated Cl(−) channel inhibition ameliorates acute pancreatitis via the IP(3)R/Ca(2+)/NFκB/IL-6 signaling pathway

TMEM16A Ca(2+)-activated Cl(−) channels are expressed in pancreatic acinar cells and participate in inflammation-associated diseases. Whether TMEM16A contributes to the pathogenesis of acute pancreatitis (AP) remains unknown. Here, we found that increased TMEM16A expression in the pancreatic tissue was correlated with the interleukin-6 (IL-6) level in the pancreatic tissue and in the serum of a cerulein-induced AP mouse model. IL-6 treatment promoted TMEM16A expression in AR42J pancreatic acinar cells via the IL-6 receptor (IL-6R)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. In addition, TMEM16A was co-immunoprecipitated with the inositol 1,4,5-trisphosphate receptor (IP(3)R) and was activated by IP(3)R-mediated Ca(2+) release. TMEM16A inhibition reduced the IP(3)R-mediated Ca(2+) release induced by cerulein. Furthermore, TMEM16A overexpression activated nuclear factor-κB (NFκB) and increased IL-6 release by increasing intracellular Ca(2+). TMEM16A knockdown by shRNAs reduced the cerulein-induced NFκB activation by Ca(2+). TMEM16A inhibitors inhibited NFκB activation by decreasing channel activity and reducing TMEM16A protein levels in AR42J cells, and it ameliorated pancreatic damage in cerulein-induced AP mice. This study identifies a novel mechanism underlying the pathogenesis of AP by which IL-6 promotes TMEM16A expression via IL-6R/STAT3 signaling activation, and TMEM16A overexpression increases IL-6 secretion via IP(3)R/Ca(2+)/NFκB signaling activation in pancreatic acinar cells. TMEM16A inhibition may be a new potential strategy for treating AP.